Previously, our lab determined that outbred adult male Sprague-Dawley rats could be classified as either low or high cocaine responders (LCRs or HCRs, respectively) following an acute low dose of cocaine. Furthermore, the level of cocaine-induced locomotor activity was significantly correlated with the level of cocaine-induced dopamine transporter (DAT) inhibition within the striatum, regardless of classification as LCRs or HCRs. We have also shown previously that LCRs, but not HCRs, develop behavioral sensitization and conditioned place preference (CPP) to cocaine. The finding that LCRs develop behavioral sensitization and CPP to cocaine suggests, but does not prove, that LCRs may be more vulnerable than HCRs to not only the activating, but also the addicting effects of cocaine. Furthermore, the cellular and molecular mechanisms mediating the underlying differences between LCRs and HCRs remain unknown. Thus, I propose to examine cocaine self-administration and the contributions of DAT rapid regulation and the DA D1 receptor to individual differences in cocaine responsiveness. My specific aims are: 1. Determine the reinforcing efficacy of cocaine for LCRs and HCRs 2. Assess the ability of LCRs and HCRs to rapidly regulate DAT surface expression in response to cocaine 3. Examine the role of DA D1 receptor-mediated ERK1/2 activation in cocaine-induced behavioral sensitization in LCRs and HCRs These aims will use both behavioral and biochemical techniques to test the overall hypothesis that LCRs are more vulnerable to cocaine's activating and addicting effects, at least in part, because of an inability to rapidly regulate the DAT in response to cocaine. Cocaine's reinforcing efficacy will be analyzed with a self administration progressive-ratio schedule of cocaine reinforcement. Cocaine-induced rapid regulation of the DAT in the striatum of LCRs and HCRs will be analyzed using [3H]DA uptake kinetics and cell surface biotinylation assays. Contributions of the DA D1 receptor to cocaine-induced ERK1/2 activation and behavioral sensitization will be assessed by pretreatment with the DA D1 receptor selective antagonist SCH23390, open field activity recordings, and western blots with phospho-ERK antibodies. Relevance to Public Health: Currently there are few effective treatments for cocaine addiction. Interactions between cocaine and the DAT are critical for cocaine's effects. Research proposed here will contribute to our understanding of cocaine-induced DAT regulation and provide a potential molecular target for cocaine addiction treatments. [unreadable] [unreadable] [unreadable]